The compound N-cyclohexyl-N-methyl-(2-amino-3,5-dibromobenzyl)-amine, known as bromhexine, as well as the hydrochloride thereof, comprise an active substance which has been known for many years. The therapeutic effect of bromhexine in diseases of the respiratory tract which are accompanied by a pathological change in secretion has often been confirmed by single or double blind testing. In addition to having this effect, bromhexine also affects the coughing itself. The frequency of coughing, the total number of coughing spasms, and the intensity of the cough are favorably affected. Patients always find that their breathing is eased. For this reason, a delayed-release form with a prolonged effect would be of particular benefit for patients during the night, since it would avoid the subtherapeutic levels in the blood caused by the long interval between doses of bromhexine preparations which do not have delayed release.
In addition to being useful in the treatment of annually recurring acute tracheobronchitis, bromhexine has also proven suitable for the treatment of chronic bronchitis, bronchial asthma, and chronic sinusitis, the treatment and alleviation of which require long periods of therapy. Here again, a reduction in the number of doses required per day improves patients' compliance, which, as is well-known, is particularly important in long-term medication.
In view of the obvious advantages of producing a delayed-release form of bromhexine, there has been no shortage of attempts to produce such a preparation. However, it was found that even micronized bromhexine hydrochloride introduced into the intestinal tract by means of a preparation resistant to gastric juices did not result in any appreciable absorption. In cases such as this, success is often achieved if the active substance is mixed with an emulsifier which then releases the active substance in solubilized form in the intestinal juices. However, even with this form, it has not been possible to obtain absorption from the intestines.
Generally, to develop an effective delayed-release form, an active substance must satisfy the following conditions:
(i) good pH-independent solubility in the entire gastrointestinal tract, and PA0 (ii) no change in the speed of absorption in the absorbent part of the gastrointestinal tract.
It has been found that bromhexine does not satisfy either of these conditions. In an aqueous medium, bromhexine is soluble only in the acidic range; above a pH of 4 the substance is virtually insoluble in water. This means that bromhexine can only be dissolved and hence absorbed in the upper gastrointestinal tract, whereas, at the higher pH values which occur in the intestinal region, it remains insoluble and is not absorbed.
Since the passage time through the stomach and the upper intestinal regions (with sufficiently acid pH) is relatively short (from about 0.5 to 1 hour), it is therefore difficult to achieve absorption over several hours. Moreover, the residence period in the stomach and in the various intestinal sections can vary considerably. Thus, naturally, in the case of a substance whose solubility depends on the pH, inter-individual and intra-individual variations of levels of active substance in the blood are extremely large when the substance preparation has a slow release, as is necessary with delayed-release forms. Further, even of bromhexine is introduced in dissolved form into various intestinal sections, the absorption rate decreases sharply from the duodenum to the colon.
Normally, it is not difficult to produce delayed-release preparations with highly soluble active substances and substances which are highly soluble substantially irrespective of the pH. The delayed-release properties can be obtained, for example, by the following methods:
(1) the active substance together with excipients is formulated so that it is only released very slowly, for example, by embedding it in a matrix which dissolves extremely slowly; or
(2) the active substance together with the excipients is shaped into tablets, pellets, or the like, which are then provided with a coating which results in a slow release of the active substance.
It has been found that, even if highly soluble salts of bromhexine are used, this does not result in a delayed-release form since the extreme pH dependency of the solubility of bromhexine cannot be overcome by means of acid salts alone. If, for example, bromhexine hydrochloride is made into the form of a matrix-type delayed-release tablet (Example 11), bromhexine can only be released, in dissolved form, from this preparation as long as the tablet is in the acidic medium of the stomach. When the matrix tablet reaches the small intestine, the release of active substance and hence the absorption virtually ceases. The intestinal juices momentarily buffer the acid salts to form a substantially insoluble bromhexine base. The solubility of the bromhexine base in a phosphate buffer is shown in the following table:
TABLE 1 ______________________________________ pH Solubility (%) ______________________________________ 4.5 0.065 5.0 0.015 6.0 0.003 6.5 0.001 7.0 0.0003 ______________________________________
Understandably, in view of these extremely low solubilities and the preliminary tests in vivo mentioned above, the development of an effective delayed-release form has seemed impossible as it presupposes that bromhexine would have to be available in dissolved and absorbable form for several hours even in the pH range of the intestinal tract.